The present invention relates to the use of a TNF-xcex1 inhibitor in the preparation of pharmaceutical compositions for the treatment of nerve root injury, as well as a method for treating nerve root injury.
The object of the present invention is to obtain a possibility to treat nerve root injury induced by disk herniation, which may turn up as radiating pain into the arm or leg (sciatica), by blocking disk related cytokines.
Disk herniation is a troublesome disorder, which can cause pronounced pain and muscle dysfuntion, and thereby loss of ability to work. A herniation may occur in any disk in the spine but herniations in the lumbar and the cervical spine are most common. A disk herniation in the cervical spine may induce radiating pain and muscle dysfunction in the arm and herniation in the lumbar spine may induce radiating pain and muscle dysfunction in the leg. The radiating pain in the leg is generally referred to as xe2x80x9csciaticaxe2x80x9d. Disk herniation will cause trouble to a varying degree, and the pain may last for one or two months or in severe cases up to 6 months. The arm or leg pain that can occur as a result of disk herniation can be very intense and may thus affect the individual patient""s whole life situation during the sickness period.
U.S. Pat. No. 5,703,092 discloses the use of hydroxamic acid compounds and carbocyclic acids as metalloproteinase and TNF inhibitors, and in particular in treatment of arthritis and other related inflammatory diseases. No use of these compounds for the treatment of nerve root injuries is disclosed or hinted at.
U.S. Pat. No. 4,925,833 discloses the use of tetracyclines to enhance bone protein synthesis, and treatment of osteoporosis.
U.S. Pat. No. 4,666,897 discloses inhibition of mammalian collagenolytic enzymes by tetracyclines. The collagenolytic activity is manifested by excessive bone resorption, periodontal disease, rheumatoid arthritis, ulceration of cornea, or resorption of skin or other connective tissue collagen.
Neither of these latter two documents mentions nerve root injury or the treatment thereof.
It has now surprisingly been shown possible to be able to treat nerve root injuries, or at least alleviate the symptoms of nerve root injuries by using a pharmaceutical composition comprising an therapeutically active amount of a TNF-xcex1 inhibitor selected from the group consisting of metalloproteinase inhibitors excluding methylprenisolone, tetracyclines including chemically modified tetracyclines, quinolones, corticosteroids, thalidomide, lazaroides, pentoxyphylline, hydroxamic acid derivatives, napthopyrans, soluble cytokine receptors, monoclonal antibodies towards TNF-xcex1, amrinone, pimobendan, vesnarinone, phosphodiesterase III inhibitors, lactoferrin and lactoferrin derived analogous, and melatonin in the form of bases or addition salts together with a pharmaceutically acceptable carrier.
The therapeutically effective amount is a dosage normally used when using such compounds for other therapeutic uses. Many of these drugs are commercially known registered drugs.
Compounds that possess this activity are tetracyclines, such as tetracycline, doxycycline, lymecycline, oxytetracycline, minocycline, and chemically modified tetracyclines dedimethylaminotetracycline, hydroxamnic acid compounds, carbocyclic acids and derivatives, thalidomide, lazaroides, pentoxyphylline, napthopyrans, soluble cytokine receptors, monoclonal antibodies towards TNF-xcex1, amrinone, pimobendan, vesnarinone, phosphodiesterase III inhibitors, lactoferrin and lactoferrin derived analogous, melatonin, norfloxacine, ofloxacine, ciprofloxacine, gatifloxacine, pefloxacine, lomefloxacine, and temafloxacine. These can be present as bases or in the form of addition salts, whichever possesses the best pharmaceutical effect, and best property to be brought into a pharmaceutical suitable composition.
After previously being considered as just a biologically inactive tissue component compressing the spinal nerve root at disc herniation, the nucleus pulposus has recently been found to be highly active, inducing both structural and functional changes in adjacent nerve roots when applied epidurally (24, 37, 38, 41, 42). It has thereby been established that autologous nucleus pulposus may induce axonal changes and a characteristic myelin injury (24, 38, 41, 42), increased vascular permeability (9, 44), intra vascular coagulation (24, 36), and that membrane-bound structure or substances of the nucleus pulposus-cells are responsible for these effects (24, 37). The effects have also been found to be efficiently blocked by methyl-prednisolone and cyclosporin A (2, 38). When critically looking at these data, one realizes that there is at least one cytokine that relates to all of these effects, Tumor Necrosis Factor alpha (TNF-xcex1). Further, the active component comprises a substance inhibiting a compound triggered by the release of TNF-xcex1, such as interferon-gamma, interleukin-1, and nitrogen oxide (NO) in the form of base or addition salts.
The invention further relates to a method for inhibiting the symptoms of nerve root injury.
The effects of doxycycline, soluble cytokine-receptors, and monoclonal cytokine-antibodies have been studied and the methods used and results obtained are disclosed below.